The mortality rates in untreated pemphigus and pemphigoid patients may reach 100% and 30% respectively. The current therapy is associated with a high morbidity. Pathogenetic mechanisms are unknown. The cutaneous hallmark in both conditions is vesicles or bullae which are formed as a result of an epidermal cell-to-cell (pemphigus) or cell-to-basement membrane (pemphigoid) defect in cell adhesion. In addition, these patients produce autoantibodies against epidermal cell surface antigens; i.e., basal cells in pemphigoid and differentiating keratinocytes in pemphigus. Moreover, these antigens appear to be immunologically related. This proposal explores the effects of the autoantibodies and purified pemphigus and pemphigoid antigens on epidermal cells in vitro. The pathogenicity of these antibodies to cultured epidermal cells will be monitored by cell adhesion assays. Preliminary studies from our and other laboratories indicate that pemphigus and pemphigoid antibodies impair adhesion of cultured epidermal cells. The in vitro effects of pemphigus and pemphigoid antibodies and the serologic cross reactivity of these antigens led us to postulate that pemphigus and pemphigoid antigens are related surface markers of epidermal differentiation and "mediators" of normal epidermal cell adhesion. Isolation and immunochemical characterization of these antigens will provide a set of powerful biochemical tools to explore epidermal cell surface metabolism during differentiation and to study their biological effect on epidermal cell adhesion in vitro. It is known that certain purified cell surface antigens promote specific cell aggregation in vitro when added to cells bearing such antigens, but antibodies against these antigens block the aggregation. Therefore, we believe that the systematic study of epidermal cell adhesion using the cell surface antigen/antibody system provided by patients suffering from pemphigus and pemphigoid as probes may reveal information on the mechanisms governing these phenomena both in normal and disease states. However, these studies can be performed only when purified antigens and antibodies are available. Isolated antigens will be used 1) to develop a radioimmunoassay, 2) to stimulate human lymphocytes from normal & diseased patients.